Injection catheter for delivering a therapeutic agent into a substrate

ABSTRACT

The invention relates to an injection catheter for delivering a therapeutic agent into a substrate, comprising one or more lumens and a curved delivery element, said lumen serving as a guide for said curved delivery element outside of the substrate; said curved delivery element comprising openings on its distal tip, said distal tip comprising a distal zone and a proximal zone, said injection catheter being characterized in that the specific surface in said distal zone of said distal tip of said curved delivery element is higher than the specific surface in said proximal zone of said distal tip of said curved delivery element. The invention also relates to a process for delivering a therapeutic agent into a substrate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/265,961, filed Dec. 13, 2011, which is a 35 U.S.C. § 371 NationalPhase Entry Application of International Application No.PCT/EP2010/055869 filed Apr. 29, 2010, which designates the U.S., andwhich claims benefit of Belgium Application No. BE2009/0271 filed Apr.29, 2009 and claims benefit under 35 U.S.C. § 119(e) of U.S. ProvisionalApplication No. 61/312,371 filed Mar. 10, 2010, each of which is herebyincorporated by reference herein in its entirety.

TECHNICAL FIELD

The invention relates to the field of injection catheters. Morespecifically, the invention relates to an injection catheter fordelivering a therapeutic agent into a substrate and a process forinjecting a therapeutic agent into a substrate.

DESCRIPTION OF THE STATE OF THE ART

Cardiovascular diseases are among the principal causes of death in theworld. Heart attacks and myocardial infarction may cause immediate deathor a relatively high morbidity rate, considering the irreversible damagecaused to the heart. The prevention and treatment of these diseases arethus a major issue and numerous clinical efforts are being made toimprove the care and treatment of cardiac disorders.

Regenerative medicine is one of the current research methods forreducing dysfunction of organs, such as the heart, for example (Sherman,Cellular Therapy for Chronic Myocardial Disease: Nonsurgical approaches,Basic Appl. Myol. 13(1) 11-14). This involves the injection oftherapeutic solutions directly into the organ through devices. Suchtherapy is promising but requires some optimizations. One of thelimitations is the low rate of retention of the therapeutic solutionsinjected into the organ, due to its porosity. In the case of the heartmuscle, this rate of retention varies but does not exceed 5 to 10%depending on the injection methods used (Bartunek et al., Delivery ofBiologics in Cardiovascular Regenerative Medicine, Clinical Pharmacology& Therapeutics, 2009). This low rate of retention thus implies anon-optimal efficiency of these therapeutic solutions. In addition,during the comparative tests conducted by inventors, a device of theprior art, the Myostar® device developed by Biosense-Webster, wasevaluated and showed a retention of around 25,000 microspheres per gram(see FIG. 8 and its description). This level of retention is not optimalfor therapeutic agent delivery and can be markedly improved.

Therapeutic solutions are generally administered with the help ofmedical devices such as injection catheters, for example, whoseconfiguration directly affects the efficiency and the quality of theinjection. Heldman et al., Cell Therapy for myocardial infarction:Special delivery, Journal of Molecular and Cellular Cardiology, 2008,44, 473-476, describes the disadvantages of several delivery deviceslisted according to type of injection (epicardiac, endocardiac,intracoronary or intravenous). Within the framework of an endocardiacinjection, the risk of perforation of the heart muscle is accentuatedbecause such a complication may lead to the patient's death.

EP 1 301 228 discloses a deployment device intended for the heart. Thedevice is an injection catheter whose tip in contact with the heartmuscle is fitted with a hole on one of its faces. Cellular material maythen be ejected into the heart muscle through said hole. However, thecellular material is injected at a precise isolated point in the heartmuscle that does not aid in its dissemination. Furthermore, when the tipis withdrawn, some of the cellular material may be released in theventricle. In addition to a low rate of retention in the heart tissueand a risk of perforation of the heart muscle, the injection at anisolated point may promote the formation of edema.

US 2007/005018 discloses a direct injection catheter device comprised ofa hollow insertion tube (410) fitted with curved elements (310) equippedwith regular openings (734) at their tip. Said elements are used toanchor the insertion tube in the heart muscle and partially reduce therisk of perforation through it. The regular openings placed on saidelements serve to inject the therapeutic solution at a low speed.However, the proposed device does not allow the injection pressure andthe dissemination of the therapeutic solution within the heart muscle tobe controlled.

WO 01/45548 discloses a straight injection needle comprising a porousdistal portion creating a gradient of hydraulic impedance on liquidmoving through the pores of the distal portion. The injection needle canbe connected to a surgical instrument. To achieve the delivery of theliquid with the hydraulic impedance, the porous distal portion has, inany event, porosity in the range from 50% to 85%. However, a needlehaving porosity higher than 20% may lack rigidity to provide asatisfactory deployment within a substrate, such as a biological tissue.Moreover, the injection needle is not provided with means to avoid theperforation of the substrate or for anchoring it into the substrateduring the delivery. Hence, the delivery of a liquid cannot be properlyperformed with such injection needle, particularly in a beating heartmuscle. In addition, the rate of injection is in the range from 0.1 ccper second to 2 cc per second. Such injection rate is not suitable forinjecting therapeutic agent comprising cells since the membrane of thecells will be damaged.

There is thus a need for an injection catheter capable of delivering atherapeutic agent into a substrate as said therapeutic agent isdisseminated in said substrate, while still minimizing the losses ofsaid therapeutic agent when the catheter needle is withdrawn and therisk of perforation of said substrate, while at the same time maximizingthe retention of said therapeutic agent in said substrate. There is alsoa need for an injection catheter capable of delivering a therapeuticagent into a substrate while still limiting the risk of edema at theinjection site.

SUMMARY OF THE INVENTION

The present invention overcomes all or some of the drawbacks anddisadvantages of conventional techniques and may also offer otheradvantages not envisaged with conventional devices.

According to a first aspect of the invention, an injection catheter fordelivering a therapeutic agent into a substrate is provided. Saidinjection catheter consists of one or more lumens and a curved deliveryelement, said one or more lumens serving as guide for said deliveryelement outside of the substrate, said delivery element comprisingopenings at its distal tip, said distal tip consisting of a distal zoneand a proximal zone; said injection catheter is characterized in thatthe specific surface of said openings of said distal zone is higher thanthe specific surface of said openings of said proximal zone. A specificsurface increasing between said proximal zone and said distal zoneallows for better retention of the therapeutic agent in the substratedue to the optimal distribution of said therapeutic agent in saidsubstrate.

According to a second aspect of the invention, a process for deliveringa therapeutic agent into a substrate through an injection catheteraccording to the invention is provided. Said process comprises the stepsof:

-   -   positioning the distal tip of said injection catheter on the        surface of the substrate,    -   sliding said curved delivery element inside said one or more        lumens and extending it inside the substrate,    -   injecting the therapeutic agent into the substrate through said        curved delivery element.

According to another aspect, the invention relates to the use of theinjection catheter, according to the invention, for delivering atherapeutic agent into a substrate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A represents a schematic view of an injection catheter accordingto a particular embodiment of the present invention.

FIG. 1B represents a cross-section of a delivery element according to aparticular embodiment of the present invention.

FIG. 2 represents a view of a delivery element comprising slits with asurface increasing in the distal direction.

FIG. 3 represents a view of a delivery element comprising circularopenings with a diameter increasing in the distal direction.

FIG. 4 represents a view of a delivery element comprising rhomboidalopenings with a surface increasing in the distal direction.

FIG. 5 represents a view of a delivery element comprising rectangularopenings with a surface increasing in the distal direction.

FIG. 6 represents a view of a delivery element comprising slit shapedopenings.

FIG. 7 represents a schematic view of a delivery element whose distaltip is comprised of two zones having different density of openings.

FIG. 8 represents a chart showing the retention capacity of a modelsolution of therapeutic agent in a substrate at an injection site. Themicrospheres were injected by various medical devices.

FIG. 9 represents a chart showing the retention of GFP-cells per gram atinjection sites for three injection catheters.

FIG. 10 represents a view of a delivery element comprising sevencircular openings with a diameter increasing in the distal direction.

DETAILED DESCRIPTION OF THE INVENTION

The term “catheter”, as used here, refers to a tubular medical devicefor insertion into a duct, a body cavity, veins or arteries in order toallow for the injection or withdrawal of fluids or to keep a pathwayopen.

The term “lumen” refers to the opening or the inside space of a hollowtubular element facilitating the insertion of a second element or theinjection of a liquid in a duct, a body cavity, veins or arteries.

The term “delivery element” as used here refers to a tube with a distalopening; a proximal opening on which a cap also called “luer lock” maybe adapted. This cap serves to close the proximal opening of thedelivery element in a secured manner.

The term “specific surface” refers to the sum of the surfaces of theopenings present in a predefined zone of the distal tip of a deliveryelement, in relation to the delivery element's unit of length.Hereinafter, the specific surfaces are expressed in mm² of opening permm of length of delivery element.

The substrate has a thickness E. Referring to FIG. 1A, the curveddelivery element 2 penetrates the substrate 12 to a depth that variesaccording to the point P of the delivery element being considered. Theshortest possible distance between the point P being considered and thesurface of the substrate is the depth D. The maximum depth Dmax islocated at the point Pmax for which the distance D is the greatest. Theterm “penetration depth” refers to the relation, expressed as apercentage, between the maximum depth Dmax and the thickness of thesubstrate E.

FIG. 1A represents a schematic view of the distal tip 4 of the curveddelivery element 2. The injection catheter 1 is positioned on thesubstrate 12 and comprises a lumen 14 in which a delivery element 2 isdeployed. The distal tip 4 of the delivery element 2 comprises openings6 on at least one side. The delivery element is curved. The distal tip 4comprises a proximal zone 8 and a distal zone 10. Said distal zone 10 iscomprised of at least one opening 6. Said distal zone 10 may be locatedanywhere along the distal tip 4 on the condition that it is closer tothe distal opening 22 than said proximal zone 8. The distal opening 22is not considered to be an opening 6 according to the present invention.Said distal zone 10 and said proximal zone 8 have identical dimensions.The length of the distal tip 4 corresponds to the distance between theopening closest to the distal opening 22 and the opening farthest fromsaid distal opening 22. The distal tip may not exceed three centimeters.

FIG. 1B represents a cross-section of the curved delivery element 2 atthe level of the distal tip 4. Said curved delivery element has an innerdiameter ID and an outer diameter OD. Said delivery element is comprisedof an opening 6. The opening 6 has a three-dimensional shape with anouter surface 24 and an inner surface 26, and extends to a height H. Theterm “surface” used in the present invention refers to the outer surface24 of the opening 6. The opening may have an inner surface 26 that isequal to, larger than or smaller than the outer surface 24. The shape ofthe opening as described in the invention is the shape at the level ofthe outer surface 24 of said delivery element 2.

According to a first aspect, the present invention relates to aninjection catheter 1 for delivering a therapeutic agent into a substratecomprising one or more lumens 14 and a curved delivery element 2, saidone or more lumens serving as guide for said curved delivery element 2outside of the substrate 12, said curved delivery element 2 comprisingopenings 6 at its distal tip 4, said distal tip 4 comprising a distalzone 10 and a proximal zone 8, said injection catheter 1 beingcharacterized in that the specific surface of said openings 6 in saiddistal zone 10 of the distal tip 4 of said curved delivery element 2 ishigher than the specific surface of said openings 6 in said proximalzone 8 of the distal tip 4 of said curved delivery element 2. A specificsurface of said openings 6, increasing between said proximal zone 8 andsaid distal zone 10, makes it possible to establish a controlleddistribution of the therapeutic agent inside the substrate, which willresult in better retention of said therapeutic agent in the substrate.Said curved delivery element comprises a plurality of openings at itsdistal tip. The number of openings may vary between 2 and 100,preferably between 2 and 50 and more preferably between 2 and 20. Thenumber of openings can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19 or 20, or a value comprises in the range set by twoof any of the above-mentioned values. Preferably, the injection cathetermay comprise one lumen. When the delivery element 2 is contained in thecatheter lumen 14, the delivery element is maintained under asubstantially straight straight form. When deployed into the substrate,the delivery element 2 takes its curved shape.

In an embodiment, the specific surface of said openings 6 in said distalzone 10 and in said proximal zone 8 of said distal tip 4 may be between0.01 mm²/mm and 0.25 mm²/mm, and more preferably between 0.015 mm2/mmand 0.1 mm²/mm.

In a preferred embodiment, the specific surface increases between saidproximal zone 8 and said distal zone 10 through the increase in the meansurface of the openings 6 between said proximal zone 8 and said distalzone 10 of the distal tip 4 of said curved delivery element 2. The term“mean surface” refers to the sum of the surfaces of said openings 6 in azone is under consideration divided by the number of said openings 6 inthe zone under consideration, that is, the proximal zone 8 or the distalzone 10 of said distal tip 4 of the curved delivery curved element 2.Preferably, the mean surface of said openings 6 may be between 0.001 mm²and 0.06 mm². More preferably, the mean surface of said openings 6 maybe between 0.007 mm² and 0.02 mm².

In another preferred embodiment, the specific surface increases betweensaid proximal zone 8 and said distal zone 10, through the increase inthe density of said openings 6 between said proximal zone 8 and saiddistal zone 10. The term “density” refers to the number of openings permm² of surface of the curved delivery element 2 in a predefined zone,that is, the proximal zone 8 or the distal zone 10. Thus, the density ofsaid openings 6 in said distal zone 10 and in said proximal zone 8 maybe between 0.04 openings/mm² and 25 openings/mm².

In another preferred embodiment, the specific surface increases betweensaid proximal zone 8 and said distal zone 10 through the increase in thedensity and the mean surface of said openings 6 in said proximal zones 8and distal zones 10.

In another preferred embodiment, the specific surface increases betweensaid proximal zone 8 and said distal zone 10 through the increase in thetotal surface of the openings 6. The total surface of the openingsrefers to the sum of the surfaces of each opening 6 in said zone underconsideration, such as said distal zone 10 and said proximal zone 8, forexample. The total surface of the openings in a zone, such as theproximal zone 8 and the distal zone 10, for example, may be between0.001 mm² and 1.5 mm². In said distal 10 and proximal zones 8, thesurface of the openings may be regular, increasing or decreasing in adistal direction over all or part of said zones on the condition thatthe specific surface of said openings in said distal zone 10 is higherthan that of said openings in said proximal zone 8.

In a preferred embodiment, said openings 6 may have various shapes suchas oval, square, circular, rectangular, triangular, ellipsoid or theymay also be slit-shaped, rhomboidal, spiral or helical. Said openings 6may be located anywhere along all of the faces of the distal tip 4 ofsaid curved delivery element 2. In addition, said openings may allowcells with a diameter of 10 to 1560 μm to pass through.

In another preferred embodiment, the injection catheter 1 also includesa means of controlling the penetration depth of said delivery elementinto the substrate. The presence of said means of control has made itpossible to avoid and circumvent the problems related to the risk ofperforation of the substrate. Thus, said means of control make itpossible, in a controlled manner, to maintain the penetration depth atbetween 25% and 75% of the thickness of said substrate. The therapeuticagent may thereby be injected into the substrate in complete safety.

In particular, said means to control the penetration depth may be acurved element with shape memory, an element equipped with a stop or anelement detectable by ultrasound or radiodetectable techniques such asfluoroscopy, for example. Taking its configuration into account, theinjection catheter, according to the invention, may penetrate thesubstrate to a significant distance, de facto increasing the surface ofthe substrate treated with the therapeutic agent. The increase in thesurface of the substrate in contact with the therapeutic agent has madeit possible to increase its availability in the substrate and therebyaffects the overall retention of said therapeutic agent in thesubstrate.

Preferably, said means of controlling the penetration depth may be acurved element with shape memory. In particular, said curved elementwith shape memory may be said curved delivery element 2 comprised ofopenings 6 at its distal tip 4, said distal tip 4 comprised of a distalzone 10 and a proximal zone 8, said curved delivery element 2 beingcharacterized in that the specific surface of said openings 6 of saiddistal zone 10 is higher than the specific surface of said openings 6 ofsaid proximal zone 8. Thus, the penetration depth of said curveddelivery element 2 in the substrate is controlled by its curvature. Thecurvature of said curved delivery element 2 is defined by the anglebetween the longitudinal axis going through the center of said lumenwhen the injection catheter is positioned on the substrate and thelongitudinal axis going through the center of the distal opening 22after deployment of said curved delivery element 2 in the substrate.Preferably, the angle may be between 60° and 120°, more preferablybetween 80° and 120°. In particular, the angle may be between 85° and100°. Preferably, the curvature of the distal tip 4 may be constant.

Alternatively, said means of controlling the penetration depth may be anelement equipped with a stop, not shown in the figures. In particular,said element equipped with a stop may be said curved delivery element 2.Thus, said curved delivery element 2 may be equipped with a stop placedat its proximal tip to determine its penetration depth in the substrate.

Alternatively, said means of controlling the penetration depth may be anelement detectable by ultrasound or radiodetectable techniques such asfluoroscopy, for example. In particular, said detectable element may besaid curved delivery element 2 comprised of openings 6 at its distal tip4, said distal tip 4 comprised of a distal zone 10 and a proximal zone8, said curved delivery element 2 being characterized in that thespecific surface of said openings 6 of said distal zone 10 is higherthan the specific surface of said openings 6 of said proximal zone 8.

According to a preferred embodiment, said injection catheter maycomprise anchoring means to avoid the removal of the curved deliveryelement during the delivery of the therapeutic agent. Said anchoringmeans can be the curved delivery element.

The delivery element can be retractable. The delivery element canretract when force is not exerted on the push button, disposed aroundthe luer lock, due to an opposite force being exerted by a springlocated distally of the luer lock.

According to a preferred embodiment, said curved delivery element 2 maybe a hollow needle or a sleeve positioned around a piercing element.Said curved delivery element may have an outer diameter between 20 gaugeand 34 gauge, preferably between 25 gauge and 32 gauge. Thus, the outerdiameter of said delivery element may be 0.184 mm and 0.908 mm.Preferably, the outer diameter of said delivery element may be between0.235 mm and 0.514 mm. Generally, the inner diameter of said deliveryelement may be between 0.0826 mm and 0.603 mm; preferably the innerdiameter may be between 0.108 mm and 0.260 mm. The length of thedelivery element may be greater than 100 cm from its distal opening 22to its proximal tip. For example, the length of the delivery element maybe approximately 120 cm. The inner and outer diameter of the section ofthe delivery element which penetrates the substrate may be uniform.

According to a preferred embodiment, the total surface of the openings 6on the distal tip 4 of said curved delivery element 2 may be between0.002 mm² and 3.0 mm². The term “total surface of the openings 6 on thedistal tip 4” refers to the sum of the surfaces of each openingcomprised on the distal tip of the delivery element. More preferably,the total surface of the openings 6 of the distal tip 4 may be between0.2 mm² and 3.0 mm², most preferably between 0.3 mm² and 2.0 mm².Alternatively, the total surface of the openings 6 of the distal tip 4may be between 0.02 mm² and 3.0 mm². Thanks to these mean surface valuesof said openings, the therapeutic agent is distributed regularly withinthe substrate, allowing for better assimilation of said therapeuticagent in the substrate and thereby avoiding the formation of edema atthe level of the injection site.

According to a preferred embodiment, the curved delivery element 2 maybe a hollow needle. Said hollow needle may comprise a sharp point topenetrate the substrate 12. Said hollow needle may be a material withshape memory. The term “material with shape memory” refers to a materialhaving the capacity to remember its initial shape and to return to iteven after deformation. The material with shape memory may be a nickeland titanium alloy, a copper-based, a cobalt-based, a chromium-based oran iron-based alloy. Preferably, the material with shape memory may be anickel and titanium alloy such as NiTINOL, for example. The nickel andtitanium alloy may also contain a small quantity of copper, iron,niobium, palladium or platinum. According to a preferred embodiment, thedistal tip of said hollow needle is comprised of said openings.Preferably, the distal tip of said hollow needle has an open surface ofbetween 0.5% and 30%; more preferably, the distal tip of said hollowneedle has an open surface of between 2% and 20%. The term “opensurface” corresponds to the percentage of the total surface of saidopenings compared to the total surface of the distal tip of saiddelivery element. Such an open surface allows for optimal use of theinjection catheter, according to the invention. Said hollow needleremains sufficiently rigid to be able to penetrate the substrate whilemaximizing the introduction of the therapeutic agent into it. Beyond20%, said needle loses rigidity and prevents its satisfactory deploymentwithin the substrate. Below 2%, the small specific surface of theopenings does not allow for controlled distribution of the therapeuticagent and reduces its retention to a minimum within the substrate.

According to another preferred embodiment, the delivery element may be asleeve positioned around a piercing element. Said piercing elementserves to perforate the substrate and to guide the sleeve inside thesubstrate. Said piercing element may be a material with shape memory asdefined above. In this configuration, said openings are positioned onthe distal tip of said sleeve. The distal tip of said sleeve is thusequal to said distal tip 4 of said curved delivery element 2 as definedabove. Said sleeve may be made of a polymer material, a compositematerial, a metal or an alloy. For example, said sleeve may be of, butnot limited to, polyimide, polyetheretherketone or stainless steel.Preferably, said sleeve may have an open surface higher than 2%. Morepreferably, said sleeve may have an open surface of between 2% and 50%.Said sleeve may thus have an open surface higher than 20%. In effect,thanks to its configuration, when the delivery element is a sleevepositioned on a piercing element, the disadvantages associated with thelack of rigidity of a delivery element having an open surface higherthan 20% are avoided.

The injection catheter may be equipped with a pump controlling theinjection pressure of the therapeutic agent. The presence of said pumpmakes it possible to maintain a constant pressure at the proximal tip ofthe injection catheter. Constant pressure during the injection andcontrolled distribution of the therapeutic agent through said openingspresent at the distal tip of the delivery element make it possible tominimize, limit and even avoid the risk of edema located at the level ofthe points of injection. In addition, the injection flow rate of thetherapeutic agent through the catheter may not be too high. Thus,according to a preferred embodiment, the injection flow rate may be lessthan 6 ml per minute; preferably, the injection flow rate may be lessthan 3 ml per minute.

According to another preferred embodiment, the specific surface is ofthe openings may increase in a linear manner. Preferably, thedistribution of the openings on said distal tip may be homogenous. Theterm “homogenous” refers to identical spacing between two openings. Thespacing between two openings is calculated between the centers of saidtwo openings.

According to a second aspect, the present invention relates to a processfor delivering an agent into a substrate through an injection catheteraccording to the invention, characterized in that it comprises thefollowing steps:

-   -   positioning the distal tip 4 of said injection catheter 1 on the        surface of the substrate 12,    -   sliding said curved delivery element 2 of said injection        catheter 1 inside the lumen 14 and deploying it inside the        substrate 12,    -   injecting the therapeutic agent into the substrate 12 through        said curved delivery element 2.

According to a preferred embodiment, the injection catheter may beequipped with a pump controlling the pressure of the injection of thetherapeutic agent. The presence of said pump makes it possible tomaintain constant pressure at the distal tip of the curved deliveryelement. According to a preferred embodiment, the pressure exerted bythe pump on the proximal tip of the catheter to deliver the therapeuticagent is substantially constant for the duration of the curved deliveryof said therapeutic agent. Constant pressure of the injection andcontrolled distribution of the therapeutic agent makes it possible tominimize, limit and even avoid the risk of edema located at the level ofthe injection points. In addition, the injection flow rate of thetherapeutic agent through the catheter may not be too high. Thus,according to a preferred embodiment, the injection flow rate may be lessthan 6 ml per minute; preferably, the injection flow rate may be lessthan 3 ml per minute. The injection flow rate may be constant.

According to another preferred embodiment, the therapeutic agent isdelivered over a period of between 20 seconds and 3 minutes for a 1 mlquantity of agent.

According to another preferred embodiment, the process of the presentinvention may also include a step to control the penetration depth of issaid delivery element 2 into said substrate 12. Preferably, saidpenetration depth may be between 25% and 75% of the thickness of thesubstrate 12. Controlling the depth of penetration into the substratemakes it possible to avoid and to circumvent the problems associatedwith the risk of perforation of the substrate. The therapeutic agent maythereby be injected into the substrate in complete safety.

According to another preferred embodiment, said delivery element used inthe delivery process, according to the invention, comprises openings onits distal tip. Said distal tip includes a distal zone and a proximalzone, said delivery element is characterized in that the specificsurface in said distal zone of said distal tip being higher than thespecific surface in said proximal zone of said distal tip. A specificsurface of said openings, increasing between said proximal zone and saiddistal zone, makes it possible to impose a controlled distribution ofthe therapeutic agent inside the substrate, which will result in betterretention of said therapeutic agent in the substrate. According to apreferred embodiment, the specific surface in said distal zone 10 and insaid proximal zone 8 of the distal tip may be between 0.01 mm²/mm and0.25 mm²/mm.

According to a preferred embodiment, the mean surface of an opening mayincrease between said proximal zone and said distal zone of the distaltip of said delivery element. Preferably, the mean surface of saidopening may be between 0.001 mm² and 0.06 mm². More preferably, the meansurface of said openings may be between 0.007 mm² and 0.02 mm².According to another preferred embodiment, the density of said openingsmay increase between said proximal zone and said distal zone. Thus, thedensity of said openings in said distal zone and in said proximal zonemay be between 0.04 openings/mm² and 25 openings/mm².

According to a preferred embodiment, the total surface of the openingson the distal tip of said delivery element may be between 0.002 mm² and3.0 mm². The term “total surface” refers to the sum of the surfaces ofeach opening comprised on the distal tip of the delivery element. Morepreferably, the total surface of the openings of the distal tip may bebetween 0.2 mm² and 3.0 mm², most preferably between 0.3 mm² and 2.0mm². Alternatively, the total surface of the openings 6 of the distaltip 4 may be between 0.02 mm² and 3.0 mm². The increase in the surfaceof the substrate in contact with the therapeutic agent has made itpossible to improve its availability in the substrate and thereby affectthe total retention of said therapeutic agent in the substrate.

According to another preferred embodiment, said openings 6 may havevarious shapes such as oval, square, rectangular, triangular, ellipsoid,or they may also be slit-shaped, rhomboidal or spiral. Said openings maybe located anywhere on all of the faces of the distal tip of saiddelivery element.

The penetration depth of said delivery element into said substrate maybe controlled by a curved element with shape memory, an element equippedwith a stop or an element detectable by ultrasound or otherradiodetectable technique such as fluoroscopy, for example.

Preferably, the penetration depth may be controlled by a curved elementwith shape memory. In particular, said curved element with shape memorymay be said delivery element comprised of openings on at least one ofthe faces of its distal tip, characterized in that the openings having aspecific surface increasing in the distal direction on at least aportion of said distal tip of said needle. Thus, the penetration depthof said delivery element in the substrate is controlled by its owncurvature. The curvature of said curved delivery element 2 is defined bythe angle between the longitudinal axis running through the center ofsaid lumen when the injection catheter is positioned on the substrateand the longitudinal axis running through the center of the distalopening 22 after the deployment of said curved delivery element 2 in thesubstrate. Preferably, the angle may be between 60° and 120°; morepreferably, between 80° and 120°. In particular, the angle may bebetween 85° and 100°. Preferably, the curvature of the distal tip 4 maybe constant.

Alternatively, the penetration depth may be controlled by an elementequipped with a stop. In particular, said element equipped with a stopmay be said delivery element comprised of openings on at least one ofthe faces of its distal tip, characterized in that the openings having aspecific surface increasing in the distal direction on at least asection of said distal tip of said delivery element. Thus, said deliveryelement is equipped with a stop placed at its proximal tip to determinethe depth of its penetration in the substrate.

Alternatively, the penetration depth may be controlled by an elementdetectable by ultrasound or radiodetectable techniques (for exampleX-ray, fluoroscopy or magnetic resonance imaging). In particular, saiddetectable element may be said delivery element comprised of openings onat least one of the faces of its distal tip, characterized in that theopenings having a specific surface increasing in the distal direction onat least a section of said distal tip of said delivery element.

According to a preferred embodiment, said delivery element used in theprocess, according to the invention, may be a needle or a sleevepositioned around a piercing element. If the delivery element is aneedle, said needle may have an open surface of between 0.5% and 30%,preferably between 2 and 20%. In addition, said needle may be a materialwith shape memory as defined above. Alternatively, the delivery elementmay be a sleeve positioned around a piercing element. Said piercingelement serves to perforate the substrate and to guide the sleeve insidethe substrate. Said piercing element may be a material with shape memoryas defined above. Said sleeve may be made of a polymer material, acomposite material, a metal or an alloy. For example, said sleeve may beof, but not limited to, polyimide, polyetheretherketone or stainlesssteel. Preferably, said sleeve may have an open surface higher than 2%.More preferably, said sleeve may have an open surface of between 2% and50%. Said sleeve may thus have an open surface higher than 20%. In fact,thanks to its configuration, when the delivery element is a sleevepositioned on a piercing element, the disadvantages associated with thelack of rigidity of a delivery element with an open surface higher than20% are circumvented. If the delivery element is a sleeve positionedaround a piercing element, the process, according to the invention, mayalso include a step to withdraw said piercing element prior to theinjection of said therapeutic agent into the substrate.

In a third aspect, the present invention concerns the use of aninjection catheter, according to the invention, for delivering atherapeutic agent into a substrate. In a preferred embodiment, thesubstrate may be an organ. Preferably, the substrate may be themyocardium, the liver, the kidney, the pancreas, the spinal cord or thebrain. More preferably, the substrate may be the myocardium. In apreferred embodiment, the therapeutic agent may be a solution comprisedof an element having a therapeutic effect on said substrate. Forexample, the therapeutic agent may be, but not limited to, a solutioncontaining cells or macromolecules such as proteins, for example, growthhormones, drugs, natural or synthetic micro- or nano-particles. Forexample, the cells used as a therapeutic agent may have a diameter of 10to 60 μm. Alternatively, the therapeutic agent may be any agent known inthe art. Preferably, the therapeutic agent is a solution containingcells or stem cells.

EXAMPLES

The terms and descriptions used here are proposed only for illustrationpurposes and do not constitute limitations. Man skilled in the art willrecognize that numerous variations are possible in the spirit and thescope of the invention as described in the following claims and theirequivalents; in them, all terms must be understood in their broadestsense unless otherwise indicated.

FIG. 2 represents a schematic view of the distal tip 4 of the curveddelivery element 2 comprising openings 6 with surface increasing in thedistal direction according to an embodiment of the invention. The curveddelivery element 2 is a hollow needle 16. The openings are in the shapeof slits with surface increasing in the distal direction.

FIG. 3 represents a schematic view of the distal tip 4 of the curveddelivery element 2 comprising circular openings 6 with diameterincreasing in the distal direction according to an embodiment of theinvention. The curved delivery element is a hollow needle 16.

FIG. 4 represents a schematic view of the distal tip 4 of the curveddelivery element 2 comprising rhomboidal openings 6 with surfaceincreasing in distal direction, according to an embodiment of theinvention. The curved delivery element 2 is a hollow needle 16.

FIG. 5 represents a schematic view of the distal tip 4 of the curveddelivery element 2 according to an embodiment of the invention. Thecurved delivery element 2 is a sleeve 20 positioned above a piercingelement 18. Said sleeve 20 comprises inclined rectangular openings 6whose surface increases in the distal direction.

FIG. 6 represents a schematic view of the distal tip 4 of the curveddelivery element 2 according an embodiment of the invention. The curveddelivery element 2 is a sleeve 20 positioned above a piercing element18. Said sleeve 20 is comprised of slit-shaped openings 6.

FIG. 7 represents a schematic view of the distal tip 4 of the curveddelivery element 2 according to an embodiment of the invention. Thecurved delivery element 2 is a hollow needle 16 comprising openings 6whose distal tip is comprised of two zones with a different density ofopenings. The density of the openings 6 increases in the distaldirection. The specific surface of the openings 6 in the proximal zone 8is smaller than the specific surface of the openings 6 in the distalzone 10.

FIG. 10 represents a schematic view of the distal tip of a deliveryelement comprising seven circular openings with a diameter increasing inthe distal direction. The openings 6 a-g are disposed on the distal end4 of the curved delivery element 2. Opening sizing (herein the diameter)increases in linear manner from opening 6 a to 6 g and is respectively100 μm, 107 μm, 114 μm, 121 μm, 127 μm, 133 μm and 140 μm. The curvatureof the delivery element is around 90°. The penetration depth is around3.0 mm. The proximal zone 8 comprises holes 6 a, 6 b and 6 c. The distalzone 10 comprises holes 6 e, 6 f and 6 g. The length of the distal tipis about 4 mm. The length of the proximal and the distal zone is 1.133mm each. The sum of the openings surface in the proximal zone is 0.027mm². The specific surface in the proximal zone is 0.024 mm²/mm. The sumof the openings surface in the distal zone is 0.0419 mm². The specificsurface of the distal zone is 0.037 mm²/mm.

Comparative Example 1

FIG. 8 represents a chart showing the retention of microspheres at thesite where they are injected into the heart. The microspheres wereinjected through three different injection catheters. The first catheterA is the Myostar® delivery device comprised of, as a delivery element, astraight hollow needle comprised of only one opening in its distal tip.The second catheter B is an injection catheter, according to theinvention. Catheter B comprises, as a delivery device, a hollow needlewhose distal tip is comprised of five openings deployed radially. Theopenings, circular in shape, have a diameter increasing in the distaldirection. The needle has a curved shape. The angle between thelongitudinal axis running through the center of the lumen and thelongitudinal axis running through the center of the distal opening isabout 90°. In another embodiment, the angle may be around 100°. Thethird catheter C (Corkscrew) is comprised of, as a delivery element, acorkscrew-shaped, hollow needle. The needle is comprised of fivecircular openings on its distal tip, each having a diameter of 0.1 mm.FIG. 8 represents a chart displaying the capacity of retention ofmicrospheres. The retention is expressed in the number of microspheres(/10³) retained per gram of substrate, according to the injectioncatheter used. In this example, the substrate is a myocardium. Themicrospheres used are plastic balls 15 μm in diameter.

The tests were conducted on a pig myocardium ex-vivo. The heart ismounted on the PhysioHeart device (HemoLab, Eindhoven, Netherlands),which makes it possible to resuscitate the heart and keep it beatingregularly (80 to 110 beats per minute) for several hours while perfusingoxygenated blood containing glucose. The distal tip of the injectioncatheter was positioned on the surface of the substrate, and then thedelivery element of the injection catheter was slid inside the lumen anddeployed inside the substrate. A solution of microspheres was injected.The microspheres were used as a model of a standard therapeutic agent.The solution of microspheres (2 ml containing 5 million microspheres)was injected for 1 minute at a constant speed.

Using catheter A, the rate of retention did not exceed 30.103microspheres per gram of substrate, which is slightly greater than theretention obtained with the injection catheter C, with which a rate ofretention of 18.103 microspheres per gram was attained. Thanks to theinjection catheter B, according to the invention, the retention ofmicrospheres per gram of substrate attained 105.103 microspheres pergram of substrate. The rate of retention is then approximately 30% inthe isolated tissues. The retention of a therapeutic agent in thesubstrate is clearly improved thanks to the injection catheter,according to the invention.

Comparative Example 2

This comparative example aims to compare one commercially availablecatheter (Myostar supplied by Biologics Delivery System BDS—Johnson &Johnson) and two injection catheters according to the present invention.The study was based on the assessment of the fluorescent cells retentionin myocardium of swine. All swine received one transepicardial injectioninto the anterior left ventricle wall after a left thoracotomy hasexposed the heart. One injection of 50 million cells (provided byTransgenic Services, Charleroi, Belgium) in 0.5 ml was carried out ineach swine left ventricle. The cells are GFP-labeled (GFP means GreenFluorescence Protein). The experimental procedure was carried out asfollows:

-   -   T0—1 h30: premedication    -   T0—1 h15: physical evaluation and electrocardiogram    -   T0—1 h: anesthesia    -   T0—0.5 h: left thoracotomy    -   T0: one transepicardial injection in anterior left ventricle    -   T0+1 h: blood sampling and euthanasia        After euthanasia, the heart was excised and tissue samples taken        from the epicardial surface on the injection site (anterior        mid-left ventricle wall) were analyzed. The analysis was carried        out by counting, using fluorescence activated cell sorting        (FACS), GFP-labelled cells retained in said tissue. It is also        noted that during the procedure no arrhythmias was observed and        that all swine survived.

Three catheters was compared and had the following configuration:

-   -   Catheter D was the Myostar with straight needle and no side        holes.    -   Catheter E was a catheter according to the present invention.        The Nitinol needle has 100° curved distal tip and is provided        with 4 side holes.    -   Catheter F was a catheter according to the present invention.        The Nitinol wire has 100° curved distal tip and a polyimide        sheath containing 4 side holes disposed thereon.

The analysis of the tissues samples allowed the determination of theretention of cells at the injection site. The table 1 showed the averageresults from FACS analysis of tissues collected at injection site. FIG.9 is a chart showing the number of GFP-cells per gram for the injectioncatheters tested.

TABLE 1 GFP-cells per GFP-cells per Catheter 100000 cells gram D 48.2295790 E 653.2 4004388 F 175.8 1077691

These data clearly highlight that the injection catheters according tothe present invention can surprisingly and dramatically enhance theretention of cells in the myocardium. This improvement is provided bythe increasing in specific surface in distal direction as presentlyclaimed.

The invention claimed is:
 1. An injection catheter for delivering atherapeutic agent into a substrate, the injection catheter comprising:(i) a lumen that extends along the length of a longitudinal axis of theinjection catheter and having an open distal end, the lumen beingcoaxial with the longitudinal axis of the injection catheter; and (ii) acurved delivery element, wherein the curved delivery element is deployedwithin the lumen when the curved delivery element is located outside ofthe substrate, the curved delivery element taking its curved shapedistal to the open distal end of the lumen when deployed into thesubstrate through the open distal end of the lumen of the injectioncatheter, the curved delivery element including a hollow tube with adistal opening, the hollow tube having a proximal end and a distal endwherein the distal end comprises a distal tip portion, the distal tipportion of the hollow tube of the curved delivery element having atleast two side openings wherein the at least two side openings areangularly displaced from each other about a longitudinal axis of thedistal tip portion, the distal tip portion having a distal zone and aproximal zone, wherein a specific surface of the side openings in thedistal zone is greater than a specific surface of the side openings inthe proximal zone, wherein the specific surface of the side openings inthe distal zone of the distal tip portion is the sum of a surface areaof the side openings in the distal zone of the distal tip portion perunit of length of the distal zone measured along the longitudinal axisof the distal tip portion, and the specific surface of the side openingsin the proximal zone is the sum of a surface area of the side openingsin the proximal zone of the distal tip portion per unit of length of theproximal zone measured along the longitudinal axis of the distal tipportion, wherein the at least two side openings are suitable fordelivering the therapeutic agent, where the therapeutic agent includescells, and wherein the at least two side openings are configured todeliver the therapeutic agent with a flow rate that is less than 6 mlper minute.
 2. The injection catheter of claim 1, wherein the specificsurface of the side openings in the distal zone of the distal tipportion and the specific surface of the side openings in the proximalzone of the distal tip portion is between 0.01 mm²/mm and 0.25 mm²/mm.3. The injection catheter of claim 1, wherein the specific surface ofthe side openings increases in a linear manner from a proximal end ofthe distal tip portion to a distal end of the distal tip portion.
 4. Theinjection catheter of claim 1, wherein the side openings are arranged toallow for controlled distribution of the therapeutic agent.
 5. Theinjection catheter of claim 1, wherein the distribution of the sideopenings in the distal tip portion is homogeneous.
 6. The injectioncatheter of claim 1, wherein the specific surface of the side openingsincreases between the proximal zone and the distal zone by the increasein: (i) the mean surface of the side openings, or; (ii) the totalsurface of the side openings, or; (iii) the density of the number ofside openings.
 7. The injection catheter of claim 1, wherein apenetration depth of the curved delivery element in the substrate iscontrolled by the curvature of the curved delivery element, thecurvature of the curved delivery element being defined by an anglebetween about 60 degrees and about 120 degrees between the longitudinalaxis going through the center of the lumen when the injection catheteris positioned on the substrate in use and the longitudinal axis goingthrough the center of the distal opening after deployment of the curveddelivery element in the substrate.
 8. The injection catheter of claim 7,wherein further control of the depth of penetration of the curveddelivery element into the substrate is by way of an element detectableby ultrasound or other radiodetectable technique.
 9. The injectioncatheter of claim 1, wherein the curved delivery element includes ahollow needle.
 10. The injection catheter of claim 9, wherein an opensurface area of the distal tip portion of the hollow needle is between 2percent and 20 percent, wherein the open surface is the percentage ofthe total surface of the openings compared to the total surface of thedistal tip of the delivery element.
 11. The injection catheter of claim1, wherein the curved delivery element comprises a sleeve positionedaround a piercing element.
 12. The injection catheter of claim 1,wherein the cells are human cells.
 13. The injection catheter of claim12, wherein the human cells are stem cells.
 14. The injection catheterof claim 12, wherein the human cells are cardiac progenitor cells. 15.The injection catheter of claim 1, wherein the flow rate is less than 3ml per minute.
 16. The injection catheter of claim 1, further comprisinga stop coupled to the curved delivery element to aid in determining apenetration depth of the curved delivery element when deployed in thesubstrate.
 17. A method for delivering a therapeutic agent into asubstrate using the injection catheter of claim 1, the methodcomprising: positioning the open distal end of the lumen of theinjection catheter on a surface of the substrate; locating the curveddelivery element of the injection catheter inside the lumen anddeploying the curved delivery element into the substrate; and injectingthe therapeutic agent into the substrate through the curved deliveryelement.
 18. The method of claim 17, wherein a positive pressure isexerted on the proximal end of the injection catheter so as to deliverthe therapeutic agent, and where the pressure is substantially constantfor the duration of the delivery of the therapeutic agent.
 19. Themethod of claim 17, further comprising controlling the penetration depthof the curved delivery element into the substrate.
 20. The method ofclaim 19, wherein the penetration depth is between 25 percent and 75percent of a thickness of the substrate.
 21. The method of claim 17,wherein the therapeutic agent is delivered over a period of betweenabout twenty seconds and about three minutes for a one mL quantity ofthe therapeutic agent.
 22. The method of claim 17, wherein the substratecomprises the myocardium.